1例异基因造血干细胞移植患者环孢素血药浓度异常波动原因分析

Analysis of Abnormal Fluctuation of the Plasma Concentration of Cyclosporin A in One Allo-HSCT Patient

目的:探讨1例异基因造血干细胞移植(allo-HSCT)患者环孢素(CsA)血药浓度异常波动的原因。方法:采用有限取样点法评估该患者体内CsA暴露量(AUC),通过非房室模型法计算该患者CsA的体内药动学参数。用高通量基因测序方法分析影响CsA代谢的主要相关基因的遗传多态性。用反转录实时荧光定量PCR方法检测CYP3A5和ABCB1基因mRNA表达水平。并结合患者的血常规、肝肾功能等生理生化指标分析。结果:该患者夜间达峰时间为8 h(>3 h,日间达峰时间),存在吸收延迟。患者红细胞计数和总蛋白水平偏低,可能是影响CsA体内分布及其与蛋白结合的因素;肝功异常可能影响CsA代谢;肾功能正常,提示CsA排泄正常。患者的CYP3A5(rs776746)、CYP3A4(rs28371759)和ABCB1(rs1045642,rs1128503)均为变异基因型,且CsA血药浓度昼夜变化趋势与CYP3A5和ABCB1 mRNA表达变化一致。结论:该患者CsA浓度异常与患者的血细胞计数、肝肾功及代谢基因突变有关,同时亦可能受基因表达昼夜节律的影响。

Objective:To investigate the cause of abnormal fluctuation of blood concentrations of cyclosporin A(CsA)in one alloHSCT patient.Methods:The area under curve(AUC)of CsA exposure in this patient was evaluated by finite sampling point method,and the pharmacokinetic parameters of CsA in this patient were calculated by non-atrioventricular model.High throughput gene sequencing was used to analyze the genetic polymorphisms of the major genes involved in CsA metabolism.The expression levels of CYP3A5 and ABCB1 mRNA expression levels were measured by RT-PCR.At the same time,the reasons for the abnormal fluctuation of CsA concentration were analyzed by combining the blood routine,liver and kidney function and other physiological and biochemical indexes.Results:In this patient,the peak time of CsA at night was 8 h(>3 h,peak time of day),and CsA absorption was delayed.Low erythrocyte count and total protein level in this patient were the factors affecting the in vivo distribution and protein binding of CsA;abnormal liver function affected CsA metabolism;normal renal function indicated normal excretion of CsA.CYP3A5(rs776746),CYP3A4(rs28371759)and ABCB1(rs1045642,rs1128503)were the variant genotypes and the diurnal variation trend of CsA concentration was consistent with CYP3A5 and ABCB1 mRNA expression levels.Conclusion:The abnormal CsA concentration in this patient is related to the blood count,liver and kidney function and metabolic gene mutation,and may also be affected by the circadian rhythm of gene expression.